<b>Covalent adducts of melphalan with free amino acids and a model peptide studied by liquid chromatography/tandem mass spectrometry</b>

Dewaele, Debbie; Sobott, Frank; Lemière, Filip

doi:10.1002/rcm.7489

Cited by 5 publications

(5 citation statements)

References 28 publications

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“…Despite expectations of resistant cells detoxifying melphalan more efficiently, we observed minimal differences between them and their respective naïve cells. Furthermore, glutathionylated and purine adducts of melphalan were not observed in any of the cell lines; these results were consistent with previous literature describing difficulty in their synthesis and detection …”

Section: Discussionsupporting

confidence: 92%

“…In addition, no other melphalan metabolites, including drug conjugates with guanine or GSH, were detected in these experiments in either the cells or the culture media, ruling out differences in glutathionylation or other detoxification strategies. 49,50 These data indicate melphalan resistance is not dependent on changes in drug detoxification, consistent with the previously published results 34 and supporting the hypothesis that other metabolic changes are contributing to drug resistance.…”

Section: Resistant Cells Do Not Detoxify Melphalan Faster Than Nai ̈V...supporting

confidence: 91%

“…Furthermore, glutathionylated and purine adducts of melphalan were not observed in any of the cell lines; these results were consistent with previous literature describing difficulty in their synthesis and detection. 49 Higher levels of metabolites in the PPP and lower levels of guanine and guanosine in both resistant cell lines suggested improved precursor formation and purine salvage, respectively, for DNA synthesis to overcome covalent modification of guanine bases, consistent with melphalan's mechanism of action. For the 8226 and LR5 cell line pair, GSH levels in resistant cells were higher, consistent with a previously identified observation for the mechanism of action for melphalan resistance.…”

Section: ■ Conclusionmentioning

confidence: 82%

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Metabolic Changes Are Associated with Melphalan Resistance in Multiple Myeloma

et al. 2021

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Multiple myeloma is an incurable hematological malignancy that impacts tens of thousands of people every year in the United States. Treatment for eligible patients involves induction, consolidation with stem cell rescue, and maintenance. High-dose therapy with a DNA alkylating agent, melphalan, remains the primary drug for consolidation therapy in conjunction with autologous stem-cell transplantation; as such, melphalan resistance remains a relevant clinical challenge. Here, we describe a proteometabolomic approach to examine mechanisms of acquired melphalan resistance in two cell line models. Drug metabolism, steady-state metabolomics, activity-based protein profiling (ABPP, data available at PRIDE: PXD019725), acutetreatment metabolomics, and western blot analyses have allowed us to further elucidate metabolic processes associated with melphalan resistance. Proteometabolomic data indicate that drug-resistant cells have higher levels of pentose phosphate pathway metabolites. Purine, pyrimidine, and glutathione metabolisms were commonly altered, and cell-line-specific changes in metabolite levels were observed, which could be linked to the differences in steady-state metabolism of nai ̈ve cells. Inhibition of selected enzymes in purine synthesis and pentose phosphate pathways was evaluated to determine their potential to improve melphalan's efficacy. The clinical relevance of these proteometabolomic leads was confirmed by comparison of tumor cell transcriptomes from newly diagnosed MM patients and patients with relapsed disease after treatment with high-dose melphalan and autologous stem-cell transplantation. The observation of common and cell-line-specific changes in metabolite levels suggests that omic approaches will be needed to fully examine melphalan resistance in patient specimens and define personalized strategies to optimize the use of high-dose melphalan.

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Section: Discussionsupporting

confidence: 92%

Section: Resistant Cells Do Not Detoxify Melphalan Faster Than Nai ̈V...supporting

confidence: 91%

Section: ■ Conclusionmentioning

confidence: 82%

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Metabolic Changes Are Associated with Melphalan Resistance in Multiple Myeloma

et al. 2021

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“…For this reason, assays with single amino acids or model peptides have been carried out and subjected to different analytical procedures to study their characteristic ion patterns. In the case of the chemotherapeutic agent melphalan, its reactivity towards single amino acids has been recently studied [61]. Characterization of adducts with synthetic tryptic peptides from HSA has been critical for the subsequent identification of the modification sites by amoxicillin in ex vivo samples [62].…”

Section: Drug-protein Adduct Formationmentioning

confidence: 99%

Adduct Formation and Context Factors in Drug Hypersensitivity: Insight from Proteomic Studies

González-Morena¹,

Montanez²,

Aldini³

et al. 2017

CPD

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Drug hypersensitivity reactions result from the activation of the immune system by drugs or their metabolites. The clinical presentations of drug hypersensitivity can range from relatively mild local manifestations to severe systemic syndromes that can be life-threatening. As in other allergic reactions, the causes are multifactorial as genetic, metabolic and concomitant factors may influence the occurrence of drug hypersensitivity. Formation of drug protein adducts is considered a key step in drug adverse reactions, and in particular in the immunological recognition in drug hypersensitivity reactions. Nevertheless, non-covalent interactions of drugs with receptors in immune cells or with MHC clefts and/or exposed peptides can also play an important role. In recent years, development of proteomic approaches has allowed the identification and characterization of the protein targets for modification by drugs in vivo and in vitro, the nature of peptides exposed on MHC molecules, the changes in protein levels induced by drug treatment, and the concomitant modifications induced by danger signals, thus providing insight into context factors. Nevertheless, given the complexity and multifactorial nature of drug hypersensitivity reactions, understanding the underlying mechanisms also requires the integration of knowledge from genomic, metabolomic and clinical studies.

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“…We previously investigated melphalan (L-phenylalanine mustard; see Figure 1), an alkylating agent which is used in the treatment of cancer [45,46]. Several studies have been published discussing its (pharmaco)kinetics, binding to DNA and proteins [47][48][49][50], and its clinical applications. In aqueous solution, melphalan forms two major hydrolysis products [51,52] in vitro, mono-and dihydroxy melphalan, as well as chain-like oligomers [53].…”

Section: Introductionmentioning

confidence: 99%

Analyzing complex mixtures of drug-like molecules: Ion mobility as an adjunct to existing liquid chromatography-(tandem) mass spectrometry methods

Boschmans

Lemière

Sobott

2017

Journal of Chromatography A

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Please cite this article as: Jasper Boschmans, Filip Lemière, Frank Sobott, Analyzing complex mixtures of drug-like molecules: ion mobility as an adjunct to existing liquid chromatography-(tandem) mass spectrometry methods, Journal of Chromatography A http://dx.doi.org/10. 1016/j.chroma.2017.02.015 This is a PDF Þle of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its Þnal form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThe use of traveling wave ion mobility mass spectrometry (TWIMS) is evaluated in conjunction with, and as a possible alternative to, conventional LC-MS(/MS) methods for the separation and characterization of drug-like compounds and metabolites. As a model system we use an in vitro incubation mixture of the chemotherapeutic agent melphalan, which results in more than ten closely related hydrolysis products and chain-like oligomers. Ion mobility as a filtering tool results in the separation of ions of interest from interfering ions, based on charge state and shape/size. Different classes of chemical compounds often display different mobilities even if they show the same LC behavior -thereby providing an orthogonal separation dimension. Small molecules with identical or similar m/z that only differ in shape/size (e.g. isomers and isobars, monomers/dimers) can also be distinguished using ion mobility. Similar to retention times and mass-to-charge ratios, drift times are analyte-dependent and can be used as an additional identifier. We find that the compound melphalan shows two different drift times due to the formation of gas-phase charge isomers (protomers). The occurrence of protomers has important implications for ion mobility characterization of such analytes, and also for the interpretation of their fragmentation behavior (CID) in the gas phase.

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Covalent adducts of melphalan with free amino acids and a model peptide studied by liquid chromatography/tandem mass spectrometry

Cited by 5 publications

References 28 publications

Metabolic Changes Are Associated with Melphalan Resistance in Multiple Myeloma

Metabolic Changes Are Associated with Melphalan Resistance in Multiple Myeloma

Adduct Formation and Context Factors in Drug Hypersensitivity: Insight from Proteomic Studies

Analyzing complex mixtures of drug-like molecules: Ion mobility as an adjunct to existing liquid chromatography-(tandem) mass spectrometry methods

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